Tribbles homologue 2 (Trib2) was first shown to be an oncogene in AML and subsequently has been identified as an oncogene in melanoma and lung cancer. Although Trib2 is able to induce AML in a mouse model, it is not know if persistent Trib2 expression is necessary to maintain the transformed phenotype. My goal is to identify the function of Trib2 in maintaining the transformed phenotype of AML. Our published and preliminary data show that Tribbles inhibits differentiation of AML cell lines and promotes leukemia, in part, by blocking C/EBP. Thus, targeting Trib2 in Trib2-dependent AMLs will promote tumor cell differentiation, which has proven a successful strategy in treating AML, and a long-term goal of this study to inform the design of Trib2 inhibitors for the treatment of cancer The proposed studies seek to understand Trib2 in the context of abnormal gene regulation in cancer and will identify its role in regulating self-renewal, proliferation, survival, differentiaton, and cancer cell metabolism. We will test the requirement for Trib2 in maintaining AML identity by creating a murine model of Trib2-induced AML in which Trib2 expression can be conditionally regulated. We will extend our studies to human cells by employing knockdown of Trib2 by shRNA to determine whether human AML cell lines and primary AML samples that express high levels of Trib2 are sensitive to Trib2 inhibition. By demonstrating that Trib-associated AMLs require persistent Trib2 activity, our studies will validate Trib2 as a target for therapy, a findig that will likely extend to multiple other types of cancers that exhibit Trib2 dysregulation.